Cathepsin S inhibitors
a cathepsin and inhibitor technology, applied in the field of peptidyl compounds, can solve the problems of increasing the likelihood of toxicity
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example 1
Synthesis of 2-tert-butoxycarbonylamino-4,4,5,5-trimethyl-hexanoic acid
[0086]
[0087]Lithium diisopropylamide (LDA) (1.5 M solution in cyclohexane / THF / ethylbenzene) (106 mL, 160 mmol, 1.15 equiv) was syringed into a 1000 mL round-bottom flask under a blanket of Ar. Dry THF (150 mL) was added and the mixture was cooled to −78° C. with a dry-ice / acetone bath. 3,3-Dimethyl-butanoic acid ethyl ester (20 g, 23.3 mL, 139 mmol, 1.0 equiv) was added dropwise from a syringe over a 10 min period followed by stirring at −78° C. for 1 h. Methyl iodide (9.5 mL, 152 mmol, 1.1 equiv) was added dropwise from a syringe over a 10 min period and the creamy mixture was stirred for 1 h at −78° C., resulting in a very thick mixture. The dry-ice bath was removed and replaced with an ice bath at 0° C. Another 150 mL of dry THF was added followed by another addition of LDA (106 mL, 160 mmol, 1.15 equiv). The resulting mixture was stirred for 10 min and then the flask was re-immersed in a dry-ice / acetone bath....
example 2
Synthesis of 2-tert-butoxycarbonylamino-5,5-dimethyl-heptanoic acid
[0093]
[0094]3,3-Dimethyl-pent-4-enoic acid methyl ester (20.0 mL, 126 mmol, 1.00 eq) was cautiously introduced via pipet into a 2 L flask containing a suspension of LiAlH4 (3.63 g, 96 mmol, 0.76 eq) in 500 mL of anhydrous diethyl ether cooled by an ice water bath. The reaction mixture was allowed to warm to room temperature overnight while stirring, then quenched by slow addition of a saturated sodium potassium tartrate solution (150 mL). The mixture was diluted with ether (200 mL), and the organic layer was separated, dried (MgSO4), and concentrated to provide 3,3-dimethyl-pent-4-en-1-ol as a colorless liquid (11.0 g, 76% yield). This material was used without further purification; 1H NMR (CDCl3, 400 MHz) δ 1.00 (s, 6H), 1.58 (t, J=7.3 Hz, 2H), 2.07 (s, 1H), 3.59 (t, J=7.3 Hz, 2H), 4.89-4.94 (m, 2H), 5.80 (dd, J=17.3, 14.1, 1H).
[0095]Anhydrous DMSO (17.1 mL, 241 mmol, 2.5 eq) was added dropwise to a solution of oxal...
example 3
Synthesis of (S)-2-tert-butoxycarbonylamino-5,5-dimethyl-heptanoic acid
[0099]
[0100]R,R-DIPAMP cyclooctadiene Rh(I) tetrfluoroborate (190 mg, 0.25 mmol, 0.04 eq) was added to a solution of (Z)-2-benzyloxycarbonylamino-5,5-dimethyl-hepta-2,6-dienoic acid methyl ester (2.00 g, 6.30 mmol, 1.00 eq) in dry methanol (20 mL) in a Paar hydrogenation flask. The reaction vessel was evacuated and flushed with a hydrogen atmosphere three times, then vigorously shaken under 50 psi of hydrogen overnight. The reaction mixture was concentrated in vacuo then filtered through a plug of silica gel using a gradient of ethyl acetate in hexanes as the eluant to provide (S)-2-benzyloxycarbonylamino-5,5-dimethyl-heptanoic acid methyl ester as a yellow oil (1.63 g, 81% yield); 1H NMR (CDCl3, 400 MHz) δ 0.74-0.90 (m, 9H), 1.10-1.30 (m, 4H), 1.58-1.70 (m, 1H), 1.75-1.90 (m, 1H), 3.75 (s, 3H), 4.30-4.40 (m, 1H), 5.14 (s, 2H), 5.24-5.33 (m, 1H), 7.30-7.37 (m, 5H); [α]20D=+15.57 c=2.00, CHCl3.
[0101]10% Pd / C catal...
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